Conversion of amines to imines employing Polymer-Supported Sulfoxide (PSS) and Polymer-Supported Perruthenate (PSP): Synthesis of pyrrolo[2,1-c][1,4] benzodiazepines

Article abstract of DOI:10.1002/adsc.200505261

An efficient method for the oxidation of secondary amines to the corresponding imines has been developed by employing polymer-supported reagents. This protocol has been extended for the generation of a combinatorial library of substituted pyrrolo[2,1-c][1,4]benzodiazepine derivatives and provides a rapid and clean preparation avoiding conventional purification techniques.

Full text of DOI:10.1002/adsc.200505261

UPDATES
DOI: 10.1002/adsc.200505261
Conversion of Amines to Imines Employing Polymer-Supported
Sulfoxide (PSS) and Polymer-Supported Perruthenate (PSP):
Synthesis of Pyrrolo[2,1-c][1,4]benzodiazepines
Ahmed Kamal,* V. Devaiah, K. Laxma Reddy, N. Shankaraiah
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology,
Hyderabad-500 007, India
Phone: (þ91)-40-2719-3157, fax: (þ91)-40-2719-3189, e-mail: ahmedkamal@iict.res.in, ahmedkamal@ins.iictnet.com
Received: June 30, 2005; Accepted: October 24, 2005
Abstract: An efficient method for the oxidation of
secondary amines to the correspondingimines has
been developed by employingpolymer-supported re-
agents. This protocol has been extended for the gen-
eration of a combinatorial library of substituted pyr-
rolo[2,1-c][1,4]benzodiazepine derivatives and pro-
vides a rapid and clean preparation avoidingconven-
tional purification techniques.
the need for further purification, i.e., avoidingchroma-
tographic processes.
The oxidation of an amine to the correspondingimine
functionality is a very useful transformation, par-
ticularly in the field of natural products.[7] Vederas and
co-workers developed a polymer-supported sulfoxide
(PSS) for the Swern oxidation process.[8] Similarly, poly-
mer-supported perruthenate (PSP) has been prepared
by Ley and co-workers[9] for the oxidation of alcohols
to aldehydes and ketones. This reagent has been exten-
sively utilized for various applications in organic trans-
formations.[4a] The amine to imine oxidation process
that has been reported[10] by the use of activated
DMSO, has also been applied by us for the oxidation
of cyclic secondary amines to the corresponding
imines.[11] Also, TPAP is known for the oxidation of
amines to imines[12] and this process, as well, has been ex-
Keywords: combinatorial synthesis; ꢀgreenꢁ chemis-
try; oxidation of secondary amines; polymer-sup-
ported reagents; pyrrolo[2,1-c][1,4]benzodiazepines
Introduction
The use of combinatorial methods for the generation of tended for the preparation of imine-containingpyrro-
chemical libraries[1] has recently increased at a tremen- lo[2,1-c][1,4]benzodiazepines.[13]
dous pace. These methods are beingadopted by the
In recent years, there has been considerable interest in
chemical industry to prepare novel materials par- ringsystems such as pyrrolo[2,1- c][1,4]benzodiazepines
ticularly in the area of pharmaceutical chemistry and (PBDs) that can recognize and bind to specific sequen-
catalysis.[2] Solid-phase organic synthesis is a powerful ces of DNA.[14] These compounds have been produced
and rapid method for the generation of chemical libra- naturally from various Streptomyces species, that pos-
ries employinglinear synthetic sequences on polymer-
sess antitumor antibiotic activity, e.g., anthramycin.[14c]
supported substrates. This technique has greatly simpli- These compounds bind selectively in the minor groove
fied the preparation of products, however, there are sev- of the DNA while a covalent aminal bond is formed be-
eral associated problems and drawbacks that have not tween the electrophilic C11-position of the PBD and the
been completely addressed. Therefore, a somewhat nucleophilic attack of the C2-amino group of a guanine
modified strategy that allows the preparation of a large base[15] is generally responsible for the biological activi-
number of molecules in solution, in a linear or conver- ty. The DNA bindingability and anticancer activity de-
gent manner,[3] through the sequential use of polymer- pends on the type of substitution in the A and C rings as
supported reagents in a multi-step process is increasing- seen from the large number of compounds that have
ly becomingpopular. [4] The need for such a strategy is of been synthesized based on this ringsystem (Figure 1).
practical significance due to its ability to incorporate in- One of the PBD dimers (SJG-136), with an affinity for
line purification protocols such as scavenging of the re- Pu-GATC-Py, is presently under clinical evaluation.[16]
agent and by-products,[5] and catch-and-release[6] proce- Previous studies on the PBD-based compounds have
dures. This enables the possibility for the direct high- not only led to structurally modified PBDs[17] but also
throughput synthesis of molecules with higher purities to the development of new synthetic strategies,[18] in-
that could be screened for biological activity without cludingsolid-phase synthetic strategies. [19] In continua-
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Ahmed Kamal et al.
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sulfide. The PS-sulfide obtained after the oxidation
process could be repeatedly recycled and reused without
diminishingits effectiveness (after oxidation of the re-
agent with sodium periodate) and thus has potential
for application in combinatorial chemistry. However,
oxidation of secondary amines to imines employing
PS-perruthenate[9] 5 in conjunction with a co-oxidant
such as N-methylmorpholine N-oxide (NMO) gave
higher yields (Table 1). The use of stoichiometric PS-
perruthenate reagent provides a cleaner process for
the preparation of imines from amines. Moreover, this
polymer-supported reagent can be filtered and reused
in combination with a co-oxidant. Overall, the use of
polymer-supported reagents afford the desired products
free from the contamination of by-products or excess re-
agents and more importantly there is no need for time-
consumingwork-up as well as purification steps.
Figure 1. Biologically important pyrrolo[2,1-c][1,4]benzo-
diazepines.
In conjunction with our earlier studies on the use of
polymer-supported reagents[20] for the preparation of
the pyrrolo[2,1-c][1,4]benzodiazepine ringsystem, the
imine formation occurs through aza-Wittig reductive
cyclization employingsubstituted 2-azidobenzoic acid
as the startingmaterial, whereas the present methodol-
ogy employs substituted 2-nitrobenzoic acid as the start-
ingmaterial which proceeds through the oxidation of a
secondary amine to an imine. Therefore, we herein de-
scribe a new synthetic procedure for the preparation
of PBDs by employingthe polymer-supported reagents
(Figure 2). It has been observed in previous studies[11,13]
Figure 2. Polymer-supported reagents.
tion of this work it has been considered of interest to in-
vestigate the use of polymer-supported sulfoxide (4) as
well as perruthenate (5) (Figure 2) with regard to the
conversion of an amine to an imine functionality. This
protocol has also been extended to the synthesis of
imine-containingpyrrolo[2,1- c][1,4]benzodiazepines.
Results and Discussion
The reaction of various amines with polymer-supported
sulfoxide 4 and perruthenate 5 provide the correspond-
ingimines in good yields (Scheme 1) and the results are
illustrated in Table 1. It is observed that the use of PS-
sulfoxide[8] 4 takes place under normal Swern conditions
and 4 is an effective substitute for DMSO and does not
produce any of the unpleasant by-products like dimethyl
Scheme 2. Polymer-assisted solution-phase strategy for the
synthesis of pyrrolo[2,1-c][1,4]benzodiazepines. Reagents
and conditions: i) l-prolinol, 3, CH2Cl2, room temperature,
overnight, 94–96%; ii) 4, (COCl)2/Et3N, CH2Cl2, À508C to
room temperature, 3–3.5 h; iii) 5, NMO, CH2Cl2, room tem-
perature, 8–9 h; iv) 10% Pd-C, H2 (1.5 atm), C2H5OH, room
temperature, 6 h, 80%.
Scheme 1. Conversion of secondary amines to imines by em-
ployingPS-reagents. Reagents and conditions: i) 4, (COCl)2/
Et3N, CH2Cl2, À508C to room temperature for 3–5 h, 62–
78% ; ii) 5, NMO, CH2Cl2, room temperature, 8–10 h, 81–
96%.
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Synthesis of Pyrrolo[2,1-c][1,4]benzodiazepines
UPDATES
Table 1. Oxidation of secondary amines by employingPS-sulfoxide ( 4) and PS-perruthe-
nate (5).
[a]
Isolated yields.
[b]
1
Products were characterized by H NMR and mass spectroscopy.
in the solution phase that this oxidative methodology The reductive cyclization of the nitroaldehyde (10a–g)
does not endanger the stereochemical integrity at the employingPd/C affords the secondary amines ( 11a–g).
C11a position, which is extremely important with re- These amines (11a–g) have been treated with PS-sulf-
spect to biological activity. Therefore, the development oxide (4) or alternatively by PS-perruthenate (5) to af-
of a clean and efficient synthesis for pyrrolo[2,1- ford the desired imines 12a–g (Scheme 2) in yields rang-
c][1,4]benzodiazepines employingpolymer-supported
reagents based on the oxidation of cyclic secondary advantage of reuse of the PS-reagents there is an ab-
amines is of immense significance. sence of side-products and no unpleasant smell of
The synthetic route comprises of the couplingof l- DMSO, particularly when PS-sulfoxide is employed.
prolinol with the corresponding2-nitrobenzoic acids Moreover, the synthesis of pyrrolo[2,1-c][1,4]benzodia-
(8a–g). Interestingly, in the coupling reaction of proli- zepine antitumour antibiotics employingPS-reagents is
ingfrom 50–75% as shown in Table 2. Apart from the
nol to the nitrobenzoic acid by usingPS-cyclohexylcar-
bodiimide (3)[21] (as shown in Figure 2) there is an excess
of acid and urea by-products that can be simply filtered
a rapid and efficient procedure.
from the N-(2-nitrobenzyl)pyrrolidine-2-carbinols Conclusion
(9a–g). The N-(2-nitrobenzyl)pyrrolidine-2-carboxal-
dehydes (10a–g) have been obtained by the oxidation In conclusion, a clean process has been developed for
of 9a–g usingPS-sulfoxide ( 4) or PS-perruthenate (5). the conversion of the amine to the imine functionality.
Adv. Synth. Catal. 2006, 348, 249 – 254
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251

Ahmed Kamal et al.
UPDATES
Table 2. Oxidation of cyclic secondary amines (PBD) by employingPS-sulfoxide ( 4) and PS-
perruthenate (5).
[a]
Isolated yields.
[b]
1
Products were characterized by H NMR and mass spectroscopy.
Experimental Section
This process has also been extended to the synthesis of
pyrrolo[2,1-c][1,4]benzodiazepine antibiotics and fur-
ther the use of orchestrated multi-step PS-reagents has
also been demonstrated in their total synthesis. This fac-
ile preparation of imines from amines has potential for
use in combinatorial chemistry. A noteworthy aspect is
that these polymer-supported reagents can be recovered
and reused with negligible loss of activity and are enor-
mously beneficial from the environmental and econom-
ic points of view.
General Remarks
All reagents obtained were from commercial sources and used
without further purification. 1H NMR spectra were recorded at
200 MHz and chemical shifts are given in d units relative to the
tetramethylsilane (TMS) signal as an internal reference in
CDCl3. Couplingconstants ( J) are reported in Hertz (Hz).
Electron-impact (EI) mass spectral data were recorded in the
form of m/z (intensity relative to base 100) on a VG 7070H Mi-
cromass mass spectrometer at 2008C, 70 eV, with a trap current
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Synthesis of Pyrrolo[2,1-c][1,4]benzodiazepines
UPDATES
200 mA and 4 kVacceleration. Analytical TLC for all reactions
was performed on Merck prepared plates (silica gel 60 F254 on
glass).
Acknowledgements
The authors (V. D., K. L. R. and N. S.) are thankful to CSIR,
New Delhi for the award of Research fellowships.
References and Notes
Typical Procedures for Imines
Employing PS-sulfoxide: PS-sulfoxide[8] 4 was swollen in CH2Cl2
at room temperature for 30 min and then cooled to À508C. To
this cooled solution oxalyl chloride (1 equiv.) in CH2Cl2 was
added dropwise. After 1 h at that temperature, the secondary
amine (1 equiv.) in CH2Cl2 was added, and the mixture was stir-
red for 2 h before the addition of Et3N (1.5 equivs.). The mix-
ture was allowed to warm to room temperature and stirred
for 3–5 h. The resin was removed by filtration and washed
with CH2Cl2. The filtrate was washed three times with water.
The combined organic phases were dried over anhydrous Na2
SO4 and evaporated to afford the correspondingimine.
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PS-sulfoxide 4 (2.20 mmol/g, 0.52 mmol) was swollen in
CH2Cl2 (5 mL) at room temperature for 30 min and then
cooled to À508C. To this cooled solution oxalyl chloride
(66 mg, 0.52 mmol) in CH2Cl2 (1 mL) was added dropwise. Af-
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